Role of Magnesium Supplementation in Children with West Syndrome: A Randomized Controlled Clinical Trial

Objectives West syndrome is a severe epileptic encephalopathy of young age. It is characterized by a clinico-electrical triad of infantile epileptic spasms, regression or arrest of psychomotor development, and hypsarrhythmia. In the last two decades, the large progress in the development of newer antiepileptic drugs has allowed us to have a vast choice of treatment options to control spasms, although they often fail to do so. Thus, there is a need to explore other treatment options. Materials & Methods Subjects in this open-labelled randomized control trial were included newly diagnosed children of age between 3 months and 5 years of both genders. A total of 52 children were recruited and randomized into two groups: an intervention group (n=30) and a non-intervention group (n=22). Magnesium sulphate was provided for the intervention group but not for the non-intervention one. Both groups received the rest of the treatments, including adrenocorticotropic hormone and antiepileptic drugs. The follow-up period was three months, at the end of which a per-protocol analysis was performed. Results There was no significant difference in seizure control and neurodevelopmental outcome between both groups, but electroencephalogram significantly improved in the intervention group compared to the control. Also, the clinical response was better in patients with normal initial serum magnesium levels in the intervention group (p=0.003) than in other patients. Conclusion Magnesium supplementation may be helpful in children with West syndrome.


Introduction
West syndrome (WS) is a severe epileptic encephalopathy of young age. It is characterized by a clinico-electrical triad of (i) infantile epileptic spasms, (ii) regression or arrest of psychomotor development, and (iii) hypsarrhythmia (1).
Hypsarrhythmia is a slow, chaotic background with multifocal spikes of high voltage on electroencephalography (EEG) (2). This classical triad comprises variations in age of onset ranging from one month to 4 years: spasms that may be single, asymmetrical, or combined with focal seizures; asymmetrical, synchronous, or fragmented hypsarrhythmia; and psychomotor function that may be delayed, deteriorated, or normal (1). WS is one of the most typical infantile epileptic syndromes seen in pediatric neurology clinics with an age of onset mostly between 3-12 months, peaking around 5 months of age with a male preponderance (3).
There is no agreement on the optimum treatment for WS. In the last two decades, the large progress in the development of newer antiepileptic drugs has enabled us to have a vast choice of treatment options to control spasms, although they often fail to do so (4,5). Thus, there is a need to explore other treatment options.
Magnesium has antiepileptic and neuroprotective properties due to the antagonizing effect of the N-methyl-d-aspartate (NMDA) receptor (14). Magnesium is useful in various refractory epilepsies (15)(16)(17). However, there is a dearth of studies, especially randomized control trials (RCTs), on the role of magnesium in children with WS. Therefore, the present study aimed to examine the effect of magnesium on children with WS regarding seizure control, neurodevelopmental outcome, and EEG improvement through an RCT study design.  We found no significant difference between the groups after magnesium supplementation regarding clinical response/seizure control (p=0.69) and neuro-developmental outcome (p=0.09) but observed a significant difference in EEG improvement between the groups (p=0.04).

Materials & Methods
We also observed that the clinical response was better in the intervention group when they had normal initial serum magnesium levels compared to low initial serum magnesium levels (p=0.003).
However, we detected no significant difference in the non-intervention group regarding the clinical response at different serum magnesium levels (p=0.418). We also observed that patients with normal initial serum magnesium levels had complete responses compared to patients with low initial serum magnesium levels (p=0.004), meaning higher serum magnesium levels yielded a better clinical response. We detected no statistically significant difference in the response rate between the groups with normal initial serum magnesium levels.  Abbreviations: DQ-development quotient; SQ-social quotient   (14). Studies on the antiepileptic activity of magnesium have reported that in patients with epilepsy, serum magnesium levels are often low, and magnesium supplementation can be used as an adjunct to antiepileptic drugs (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Therefore, we conducted this open-labeled randomized controlled trial to examine the effect of magnesium supplementation on children with WS.
We carried out the present study with a prospective  (6,7,8,14,15 to increased bioavailability, and that they followed the patients for a longer duration of 6 months. We used the oral route for magnesium supplementation after the first 3 days of intramuscular injections, which is much safer than continuous intravenous injections, and we did not observe any serious side effects due to magnesium supplementation.
However, we used lower doses of magnesium and followed the patients for a shorter duration of 3 months. This might be the reason for the lack of significant clinical response in the intervention group and the erratic bioavailability of oral preparation.
In our study, there was no significant improvement in DQ/SQ levels in the intervention group, which contradicts the study by Zou et al. (2010) (18).
They found significant improvement in DQ/SQ levels (p<0.05) in the intervention group. Reasons may be that most of our patients (>90%) belonged to the symptomatic group and the commonest etiology was HIE, which is an irreversible process.
Another reason might be that we followed our patients for a shorter duration of 3 months.
Although the difference in the DQ/SQ level was nearly significant (p= 0.09), the overall long-term developmental outcome was not good at all, even after the successful treatment of infantile spasms.

In Conclusion
Although no significant improvement was found in seizure control and the neurodevelopmental outcome after magnesium supplementation, significant EEG improvement was observed. Also, within the intervention group, clinical response was better in patients with normal initial serum magnesium levels than in others. Thus, magnesium supplementation may be helpful in children with WS. However, more studies are required with a higher dose of magnesium supplementation, a larger sample size, and longer follow-up.